Delusional Disorder: Molecular Genetic Evidence for Dopamine

Psychosis
Kiyoshi Morimoto MD, Ph.D, Ryosuke Miyatake MD, Ph.D, Mitsuo Nakamura MD, Ph.D,
Takemi Watanabe MD, Ph.D, Toru Hirao MD, Ph.D and Hiroshi Suwaki MD, Ph.D

Department of Neuropsychiatry, Faculty of Medicine, Kagawa Medical University, Kagawa, Japan

Correspondence: Dr Kiyoshi Morimoto, Department of Neuropsychiatry, Faculty of Medicine, Kagawa Medical University,
1750-1 Ikenobe, Miki-cho, Kita-gun, 761-0793 Japan, Tel: +81-87-891-2167, fax: +81-87-891-2168, Email: neuropsy@kms.ac.jp

ABSTRACT
Since delusional disorder is characterized by mono-symptomatic paranoid
symptoms, it can be a good clinical model for investigating the dopaminergic
mechanism responsible for paranoid symptoms. We examined neuroleptic
responses, plasma homovanillic acid (pHVA) and genes of the dopamine receptor
(DR) and its synthesizing enzyme (tyrosine hydroxylase: TH) in patients with
delusional disorder and compared them with those of schizophrenic patients and
healthy controls. Results: (1) A relatively small dose of haloperidol was more
effective for delusional disorder than for schizophrenia. (2) The pretreatment level
of pHVA was higher in patients with persecution-type, but not in those with
jealousy-type delusional disorder, compared with age- and sex-matched controls.
This increased pHVA level was decreased eight weeks after successful haloperidol
treatment. (3) The genotype frequency of the DRD2 gene Ser311Cys was
significantly higher in patients with persecution-type delusional disorder (21%),
compared with schizophrenic patients (6%) or controls (6%). (4) Patients
homozygous for the DRD3 gene Ser9Ser had higher pretreatment levels of pHVA
than those heterozygous for Ser9Gly. (v) A significant positive correlation was
found between the polymorphic (TCAT)n repeat in the first intron of the TH gene
and pretreatment levels of pHVA in delusional disorder. We suggest that
delusional disorder, especially the persecution-type, includes a "dopamine
psychosis," and that polymorphism of the DRD2, DRD3 and/or TH gene is part of
the genetic basis underlying the hyperdopaminergic state that produces paranoid
symptoms. Further studies on a large sample size are required.
Keywords: Delusional disorder; Dopamine psychosis; pHVA; Polymorphism; DRD2 Ser311Cys; DRD3 Ser9Gly

Although the neurobiological mechanism underlying schizophrenia has been investigated

extensively during the past few decades, its biochemical and molecular etiology remain
unclear. The long-standing "dopamine hypothesis" of schizophrenia (Carlsson 1988) is partly
supported by the action of neuroleptics, which block dopamine receptors (DRs) and improve

paranoid symptoms, such as delusion and hallucination (Seeman et al. 1976). It has further
been supported by indirect evidence that repeated administration of dopamine agonists
(e.g. amphetamine and cocaine) results in the development of paranoid symptoms in
humans (Ellinwood 1976; Sato et al. 1992) and abnormal behavior ("behavioral
sensitization") in animals (Kalivas 1993). In schizophrenic patients, dopamine agonists
aggravate paranoid symptoms (Janowski and Davis 1976; Lieberman et al. 1987); this may
be the result of an aberrant increase in dopamine release (Laruelle et al. 1996; Breier et al.
1997). However, many clinical studies on plasma and cerebral spinal fluid (CSF), DR
imaging, and postmortem brain or DR genes have failed to obtain direct hyperdopaminergic
evidence, or if such evidence has been obtained, the results have been contradictory (Davis
et al. 1991; Willner 1997; Laruelle 1998; Zakzanis et al. 1998; Harrison 1999; Soares and
Innis 1999; see also Discussion).
One of the most important reasons for these complex results may be etiological
heterogeneity of the disorder, since there is a considerable variety of clinical features of
schizophrenia, including symptoms, neuroleptic response and long-term prognosis, between
the patients. To evaluate and categorize the heterogeneity clinically, some biology-based
classifications have been proposed, for example "type I and type II syndromes" (Crow
1980), "3 syndromes" (Liddle 1987), and "deficit and non-deficit forms" (Carpenter et al.
1988).
Another methodology that may allow us to break through the heterogeneity and clarify the
role of dopamine systems in psychosis is to select a psychiatric disorder with only one target
schizophrenic symptom. While paranoid symptoms are commonly seen in various psychiatric
disorders, as known "paranoid spectrum" (Fujinawa 1981), delusional disorder, a psychosis
previously called "paraphrenia" (Kraepelin 1909; Roth 1987), is characterized by monosymptomatic paranoid symptoms without other schizophrenic symptoms. In the ICD-10
diagnostic criteria (WHO 1992), delusional disorder is diagnosed when: (1) delusions
constitute the only, or the most conspicuous, clinical characteristic; (2) it cannot be
classified as organic, schizophrenic, or affective disorder; and (3) affect, speech, and
behavior are normal. Thus, delusional disorder can be a good clinical model for investigating
the molecular genetic mechanisms for paranoid symptoms.
In the present study, we hypothesized that a hyperdopaminergic state in the brain is
responsible for producing paranoid symptoms. To test this hypothesis, we compared
neuroleptic responses between patients with delusional disorder and schizophrenia,
measured plasma levels of homovanillic acid (pHVA), a dopamine metabolite and clinical
marker of dopamine metabolism, in patients with delusional disorder before and after
neuroleptic treatment, and analyzed the polymorphism of DR and its synthesizing enzyme
gene.

METHODS
Neuroleptic Response of Delusional Disorder
Subjects Eleven patients with delusional disorder classified according to ICD-10, who were
admitted to our psychiatric ward, were studied. All patients presented the first delusional
episode without previous neuroleptic medication. The average (mean S.E.M.) age (and age
at onset) was 57.5 2.2 years (54.6 2.2 years) and the male/female ratio was 1/10.
Neuroleptic responses, including effective neuroleptic dose (haloperidol equivalent, mg/day),

duration of admission, and outcome at discharge (complete/incomplete remission) were

examined. To evaluate social function, the Global Assessment of Functioning (GAF; DSM-IV
(American Psychiatric Association 1994)) score was used. In addition, we compared the
neuroleptic responses of 15 patients with schizophrenia, who presented their first psychotic
episode and were admitted during the same period, with those of the patients with
delusional disorder. The average of age (at onset) of these schizophrenic patients was
25.1 1.4 years (22.7 1.3 years), the male/female ratio was 7/8, and the ICD-10
subtypes included 6 paranoid, 6 undifferentiated, 2 hebephrenic, and 1 catatonic type.
pHVA in Delusional Disorder
Subjects To investigate brain dopamine function, pHVA levels were measured in patients
with delusional disorder and compared with those of age- and sex-matched controls.
Thirteen neuroleptic-naive patients with delusional disorder (age at onset was 48.4 years;
male/female ratio was 4/9) were subjects in our inpatient and outpatient clinics. The
subtypes involved were: nine persecution-type and four jealousy-type. Written informed
consent to participate this study was obtained from all patients. Blood for pHVA was drawn
between 9:00 A.M. and 11:00 A.M. before starting neuroleptic treatment. The Brief Psychiatric
Rating Scale (BPRS) was used to evaluate the level of delusional psychopathology in each
patient. In addition to the pretreatment examination, in eight patients, pHVA and BPRS
scores were measured eight weeks after neuroleptic treatment with a small dose of
haloperidol (average 2.7 mg/day).
Measurement of pHVA pHVA concentrations were determined by high-performance liquid
chromatography using electrochemical detection analysis (Chang et al. 1983). The
interassay coefficients of variance were 1.2 and 1.7% for concentrations of 20 and 100
pmol/ml, respectively.
The DR and Tyrosine Hydroxylase Gene in Delusional Disorder
Subjects To investigate the possible genetic basis underlying the hyperfunction of dopamine
systems in delusional disorder, we analyzed the polymorphism of genes for DRD2 and DRD3
and their synthesizing enzyme tyrosine hydroxylase (TH). Twenty-three patients with
delusional disorder, 48 patients with schizophrenia, and 48 normal controls were studied.
Delusional patients included the subjects for our pHVA study. The age at onset was 52.3
years, male/female ratio was 4/19, and the subtypes were 19 persecution-type and 4
jealousy-type. Written informed consent to participate in the study was obtained from all
patients and normal control subjects.
Genotyping
We analyzed polymorphisms of Ser311Cys in the DRD2 gene (Arinami et al. 1994), Ser9Gly
in the DRD3 gene (Crocq et al. 1992), and variable number of tandem repeat (VNTR) in the
first intron of TH gene (Wei et al. 1995). Genomic DNA was extracted from the subjects'
peripheral blood according to a standard method. Polymerase chain reaction (PCR)
amplification was performed using 50 ng of DNA, 250 M dNTP, 1.5 mM MgCl2, 5.0 l of 10
LA buffer (TaKaRa), 0.5 units of LA Taq polymerase (TaKaRa), and 0.1 M each of the
primer, which have been described previously (Arinami et al. 1994; Crocq et al. 1992; Wei
et al. 1995) in a total volume of 50 l. Samples were amplified for an initial cycle of 1 min at
94C followed by 35 cycles, each consisting of denaturing of 30 s at 94C, annealing of 30 s
and extension of 1 min at 72C. Annealing temperatures were 65C for Ser311Cys, 55C for
Ser9Gly and 57C for (TCAT)nVNTR. For restriction fragment length polymorphism analysis

of the Ser9Gly polymorphism, PCR products were digested with units of BalI (TaKaRa) and
recommended buffer for at least 6 h at 37C. The electrophoresis was performed with 2%
agarose gel for the Ser311Cys and Ser9Gly polymorphisms, and with 20% polyacrylamide
gel for (TCAT)n VNTR.

RESULTS
Neuroleptic Response of Delusional Disorder
The onset of delusional disorder appeared to be in middle age in all patients and was much
later than for schizophrenia. A clear gender difference was also seen in delusional disorder
(female>male). A relatively smaller dose of haloperidol (4.7 mg/day) was effective in
diminishing completely delusional symptoms within a shorter period of administration (65
days) in delusional disorder as compared with schizophrenia (12.7 mg/day, 104 days). At
discharge, the GAF score was significantly higher in delusional disorder, which suggests a
better prognosis (Table 1).

Table 1
Neuroleptic Response in In-Patients with Delusional Disorder and Schizophrenia
pHVA in Delusional Disorder
Pretreatment Level of pHVA The pretreatment level of pHVA tended to be more
elevated in delusional disorder than in normal control individuals (64.5 vs. 48.9
pmol/ml, p < .1, Figure 1) and it was correlated significantly to the delusion and
hallucination BPRS score (r = 0.44, p < .02, Figure 2, Panel A). When the delusional
patients were classified into the different subtypes, the persecution-type showed a higher
level of pHVA (68.5 pmol/ml, p < .05) than the controls, while the jealousy-type did not
(55.5 pmol/ml, Figure 1).

Figure 1
The pretreatment level of plasma homovanillic acid (pHVA) in patients with
delusional disorder. pHVA was higher in persecution-type delusional patients, but
not in those with jealousy-type, compared with age- and sex-matched controls.

Figure 2
Relationship between the pretreatment level of pHVA and BPRS (A), and their
changes after neuroleptic treatment (B) in delusional disorder. A: A significant
positive correlation was found between the pHVA level and BPRS delusion and
hallucination score. B: Eight weeks after treatment with a relatively small dose of
haloperidol (average 2.7 mg/day), the increased levels of pHVA and BPRS scores were
reduced.

pHVA Level after Neuroleptic Treatment Eight weeks after neuroleptic treatment with a
small dose of haloperidol, the delusion and hallucination BPRS score improved markedly,

and five out of eight patients went into complete remission. The level of pHVA also
significantly decreased eight weeks after the successful neuroleptic treatment (Figure 2,
Panel B).
The DR and TH Gene in Delusional Disorder
DRD2 Ser311Cys The genotype frequency of DRD2 Ser311Cys was 17.4% in delusional
disorder, 6.3% in schizophrenia, and 6.3% in control subjects (Table 2). There was a
significantly higher incidence of Ser311Cys heterozygote among the persecution-type
delusional patients (21.1%, p < .05), compared with the controls; none of jealousy-type
delusional patients exhibited this genotype. The pretreatment level of pHVA tended to be
higher in Ser311Cys patients (77.8 pmol/ml, n = 4) than in Ser311Ser patients (58.6
pmol/ml, n = 9; Table 3).

Table 2
Genotype Frequency of Dopamine D2 and D3 Recepor Gene

Table 3
Association between Dopamine Receptor Gene, pHVA and BPRS Score

DRD3

Ser9Gly The genotype frequency of the DRD3 Ser9Ser gene was 47.8% in
delusional disorder (52.6% in persecution-type and 25.0% in jealousytype),
47.9% in schizophrenia, and 39.6% in control subjects (Table 2). Patients
who
were homozygous for the Ser9Ser had a higher pretreatment level of
pHVA than those who were heterozygous (85.6 vs. 51.3 pmol/ml, p < .05; Table 3).
TH VNTR There was a significant positive correlation between the polymorphic
(TCAT)n repeat in the first intron of the TH gene and pretreatment level of pHVA in
delusional disorder (r = 0.62, p < .05). Patients with the (TCAT)8 or (TCAT)9allele had higher
levels of pHVA than those with (TCAT)6 or (TCAT)7 (87.1 vs. 47.9 pmol/ml, p < .02; Table
4).

Table 4
Association between the Polymorphic (TCAT)n Repeat of TH Gene and Pretreatment
Levels of pHVA

DISCUSSION
Delusional disorder has some clinical characteristics that are quite different from
schizophrenia, such as later onset, gender difference (female > male), lack of schizophrenic
negative symptoms and preservation of social function. Furthermore, the delusional disorder
patients responded well to treatment with haloperidol despite a rather low mean dose (4.7
mg/day). Although firm conclusions cannot be drawn because of the lack of randomized
dosage assignment, this does suggest that those subjects are rather responsive to
treatment with dopamine-blocking agents (Pearlson et al. 1989, Munro and Mok 1995).

These clinical and neuropharmacological features suggest that the brain mechanisms are not
identical in these psychotic disorders, and it is hypothesized that it is primarily dopamine
function that may be disturbed in delusional disorder.
In the present study, to obtain more direct evidence to confirm this hypothesis, pHVA was
employed as a "state marker" of the disorder whereas polymorphism of the DR gene was
used as a "trait marker."
Hyperdopaminergic State Responsible for Paranoid State
While a number of previous pHVA studies have failed to obtain consistent results with regard
to schizophrenia, three main lines of evidence have been reported: (1) pHVA is correlated
positively with the severity of psychotic symptoms (Davis et al. 1985; Pickar et al.
1986; Davidson and Davis 1988); (2) in good responders pHVA decreases along with
neuroleptic treatment (Pickar et al. 1984; Pickar et al. 1986; Chang et al. 1988; Koreen et
al. 1994; Nagaoka et al. 1997); and (3) pHVA is lower in deficit-type than in nondeficittype (Davidson and Davis 1988; Ribeyre et al. 1994; Thibaut et al. 1998). From these
findings, it seems that pHVA varies depending upon the subtype and course of
schizophrenia, and it is also strongly influenced by neuroleptic treatment.
In contrast to these complicated results for pHVA, more consistent results have been
observed in psychoses with a good prognosis, which is unrelated to their conventional
diagnosis (Bowers et al. 1984; Bowers 1993; Garver et al. 1997;Ottong and Garver 1997).
For example, Garver et al. (1997) have demonstrated recently that baseline pHVA is
bimodally distributed in acute psychotic patients including those with schizophrenia,
schizophreniform disorder and psychotic affective disorder, and that high-pHVA psychotic
patients have a more rapid and complete neuroleptic response than lower-pHVA psychotics.
They have suggested that the higher-pHVA psychosis is a dopamine psychosis that may
have a familial origin.
Our pHVA study had some limitations. Time of blood sampling was not strictly controlled,
and since out-patients were included in the study, a low monoamine diet was not available.
However, our time-course study on pHVA before and after neuroleptic treatment must be
reliable because of the repeated measurements taken in the same individual. Despite the
limitations, our findings on pHVA in delusional disorder are in good agreement with Garver's
results. In our study, pretreatment pHVA levels were elevated in persecution-type patients,
positively correlated with the severity of paranoid symptoms, and normalized after
successful neuroleptic treatment. In contrast, pHVA showed large variation, especially in
jealousy-type delusional patients, suggesting heterogeneity in this diagnostic category (e.g.,
paraphrenia, paranoia and late-onset schizophrenia). It is concluded from our pHVA study
that pHVA state-dependent changes in neuroleptic-naive delusional disorder and
hyperfunction of the dopamine systems could be at least partly responsible for the brain
mechanisms underlying its paranoid symptoms.
Molecular Genetic Basis of Delusional Disorder
Our molecular genetic analysis of delusional patients revealed the possible involvement of
gene polymorphisms for DRD2 and DRD3 and its synthesizing enzyme (TH).
DRD2 Ser311Cys Arinami et al. (1994) were the first to report that the allele frequency of
the 311Cys of the DRD2 gene was about three times higher in Japanese schizophrenics than
in control subjects. These authors have since duplicated their own results in a larger

population study (Arinami et al. 1996), in which it was shown that the clinical characteristics
of schizophrenic patients with the 311Cys gene were lacking negative symptoms, going into
remission and having a family history of the disorder. Many studies, however, have failed to
duplicate these results in various races (Gejman et al. 1994; Nanko et al. 1994; Asherson et
al. 1996; Chen et al. 1996; Sasaki et al. 1996; Spurlock et al. 1998); only one study
corroborated these results (Shaikh et al. 1994). Very recently, Serretti et al.
(2000) demonstrated a significant association between the Ser311Cys variant and
delusional features in major psychoses (including delusional disorder and schizophrenia) in
Italian patients. This indicates that this mutation may be connected with delusional
symptomatology independent of diagnoses, although it does not play a major role in
conferring susceptibility to major psychoses.
The results of the study presented here demonstrated that the genotype frequency of
Ser311Cys of delusional disorder is about three times higher than in schizophrenic and
control subjects. So far, two previous studies have shown a negative association between
DRD2 Ser311Cys and delusional disorder (Sasaki et al. 1996; Serretti et al. 2000). In these
studies, different criteria (DSM) were used to diagnose the subjects, which might have
resulted in the inclusion of greater numbers of paranoia and fewer paraphrenia. In addition,
their neuroleptic responses were not clearly described. Rather, our subjects had neuroleptic
responses similar to those of Arinami's subgroup with a high incidence of 311Cys.
Since the Ser311Cys mutation has been shown to cause functional alteration of DRD2 in
vitro, such as receptor internalization (Itokawa et al. 1996) and inhibition of cAMP synthesis
(Cravchik et al. 1996), dopamine signal transmission may be increased in delusional
patients with this mutation.
DRD3 Ser9Gly After the first demonstration that homozygous Ser9Ser of the DRD3 gene
was significantly higher in patients with schizophrenia by Crocq et al. (1992), several
studies, which focused especially on the schizophrenics who were good neuroleptic
responders, have been able to duplicate it (Jonsson et al. 1993; Mant et al.
1994; Nimgaonkar et al. 1996; Shaikh et al. 1996; Spurlock et al. 1998), but many other
studies have failed (see review of Dubertret et al. (1998) and Williams et al. (1998)). Two
recent meta-analysis studies have demonstrated a slight but significant excess of
homozygous Ser9Ser in all schizophrenic patients (Williams et al. 1998), or only in the
African and Caucasian groups (Dubertret et al. 1998). On the other hand, in delusional
disorder, a significant association with Ser9Ser was reported (Di Bella et al. 1994).
Our findings on persecution-type delusional patients are similar to those of Di Bella,
although they were not statistically significant because of the small population used. More
importantly, in our results it appeared that the pretreatment level of pHVA was higher in
patients with Ser9Ser than those with Ser9Gly. Normal homozygous control subjects also
appeared to have a higher CSF HVA level (Jonsson et al. 1996). Furthermore, in a previous
in vitro study it was reported that the binding activity of DRD3 homozygous for Ser9Ser is
lower (Lundstrom and Turpin 1996).
It has been shown that DRD3 is localized in the limbic brain as autoreceptors regulating presynaptic dopamine release (Sokoloff et al. 1990). In delusional disorder, the DRD3 gene
homozygous for Ser9Ser may be one of the etiologic genes responsible for producing the
high pHVA levels observed in our study, which causes paranoid symptoms.
TH VNTR It has been reported previously that polymorphism of TH gene VNTR is related to
transcription in vitro (Meloni et al. 1998) and to catecholamine turnover in vivo (Wei et al.

1997). Several studies on schizophrenia have indicated a significant association with the
polymorphic VNTR region of the TH gene (Thibaut et al. 1997; Wei et al. 1997). Consistent
with these results, our findings in delusional patients demonstrated that the pretreatment
level of pHVA is significantly correlated to the VNTR (TCNT)n repeat, suggesting that TH
VNTR is another etiologic candidate gene for the high pHVA level.
Although further studies on a large sample size are required to confirm our tentative results,
polygenes of both the pre- and post-synaptic mechanisms of dopamine systems may be
involved in the genetic etiology of delusional disorder, especially in the persecution-type.

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